CHEMICAL STRUCTURE AND BIOLOGICAL ACTIVITY 821 



i3-Tocopherol (p-xj-lotocopherol) and 7-tocopherol (o-xjdotocopherol) are 

 only about one-half as efficacious as the a-isomer. ?n-Xylotocopherol (5,7- 

 dimethyltocol), which is not a natural product, is intermediate between a- 

 and /3-tocopherols in potency. ^^'^^■^-'^•'* 5-Tocopherol (8-methyltocol) has 

 only about 1% of the physiologic activity of a-tocopherol.^^ However, 

 Karrer and Fritzsche^* found that tolutocopherol, which has a single methyl 

 group at an undetermined location, was ineffective in 20 times the dosage 

 (40 mg.) which was active in the case of a-tocopherol.^^ 



Most of the esters of a-tocopherol have a high potency, with the excep- 

 tion of the allophanates which, as has already been pointed out, are bio- 

 logically inactive."^ As regards the esters, Demole et a/."^ have reported 

 that the acetate, propionate, and n-butyrate ha^'e an even greater effect 

 than has free a-tocopherol. Harris and his collaborators^-^' '-^ have re- 

 cently confirmed the fact that the esters have a higher biological potency 

 than do the free tocopherols. a-Tocopherol acetate was shown to have a 

 62% greater potency than the free tocopherol, irrespective of whether com- 

 parisons were made between the ester and free forms of the f?-tocopherol or 

 of the synthetic (//-tocopherol. 



Inorganic esters such as the phosphate have also been shown to be 

 biologically active, ^-^ but the ethers are wholly inactive. a-Tocopherol and 

 its acetate are completeh^ non-toxic, since they may be administered to mice 

 in amounts of 50 g. per kilogram of body weight without deleterious 

 effects. ^-^ They are also non-carcinogenic.^^'^ 



The replacement of the methyl groups on the aromatic ring by one or 

 more ethyl groups profoundly depresses the potency. Thus, 5,7-dimethyl- 

 8-ethyltocoP-'^2^ is only about 20 to 25% as effective as the trimethyl 

 derivative (1 Rat Unit = 10-16 mg.), while diethylmethyltocol^-^ is potent 

 in 10-mg. doses. 5,7-Diethyltocol and monomethyltocol (5-tocopherol?) 

 have been reported to be inactive in doses as high as 40-50 mg. daily.^^-*' 

 Tocol itself*^ in doses up to 50 mg., and 6-desoxy-a-tocopheroP^" in the 

 amount of 100 mg. per daj'', were found to be completely ineffective. A 

 number of tocopherol quinones have been prepared, but these fail to show 

 any vitamin-E-like action. ^^^~^^'' 



One compound which is of interest because it plays a dual role as a 

 x-itamin is naphthotocopherol. This compound shows vitamin E activity 



125 p. Karrer and G. Bussman, Heir. Chim. Acta, 23, 1137-1138 (1940). 



126 V. Demole, Z. Vitaminforsch., 8, 338-341 (1939). 

 12' V. Demole, Z. Vitaminforsch., 8, 341-347 (1939). 



i2« P. Karrer and O. Hoffmann, Helv. Chim. Acta, 22, 654-657 (1939). 



129 P. Karrer and O. Hoffmann, Helv. Chim. Acta, 23, 1126-1131 (1940). 



130 F. V. Werder, T. Moll, and F. Jung, Z. physiol. Chem., 257, 129-139 (1939). 

 "1 P. Karrer and A. Geiger, Helv. Chim. Acta, 23, 455-459 (1940). 



132 P. Karrer, H. Salomon, and H. Fritzsche, Helv. Chim. Acta, 21 309-313 (1938). 

 1" W. John, E. Dietzel, and W. Emte, Z. physiol. Chem., 257, 173-189 (1939). 

 "^ M. D. Wright, and J. C. Drummond, Biochem. J., 34, 32-33 (1940). 



